Hydrophobic, non-polymeric materials, particularly, highly viscous, non-polymeric liquid materials have been described as biodegradable systems for controlled release delivery of bioactive compounds (Smith and Tipton, Pharmaceutical Research, 13(9), S300, 1996). The hydrophobic non-polymeric material is generally substantially insoluble in water. The hydrophobic non-polymeric material can be a highly viscous liquid that has a viscosity of at least 5,000 cP at 37° C. and does not crystallize neat under ambient or physiological conditions. When such material is mixed with a small amount of plasticizing solvent, the mixture has much lower viscosity than that of the non-polymeric liquid material alone. This low viscosity solution can be easily formulated with a bioactive compound and the resulting low viscosity liquid formulation can be readily administered to a subject to form a highly viscous depot in-situ.
Representative examples of such in-situ forming depot systems containing the hydrophobic, non-polymeric liquid carrier materials are disclosed in the U.S. Pat. Nos. 5,747,058; 5,968,542; 6,051,558; and 6,992,065. The compositions described in these patents comprise a hydrophobic, highly viscous, non-polymeric liquid material such as sucrose acetate isobutyrate (SAIB), a water soluble or miscible organic solvent, and a bioactive substance. Such a composition can be easily prepared and administered to a subject in the form of a low viscosity solution. Once in the body, the solvent dissipates or diffuses into the surrounding tissues, which leads to the precipitation or coagulation of the non-polymeric materials to form a highly viscous gel, semi-solid, or solid depot that encapsulates the bioactive substances. Then the bioactive substance is released via dissolution, diffusion, and/or degradation of the depot.
The non-polymeric carrier materials are typically degraded through the hydrolysis of the ester or ester-like bond. The cleavage of esters is facilitated nucleophilic groups, such as amine groups, within an enzyme or other bioactive substances. This facile degradability is advantageous for medical use, but the susceptibility of the formulation to degradation also presents a major problem for preparing stable formulations. Whenever a bioactive substance is combined with the non-polymeric liquid carrier materials, that same degradation can occur through the interaction between the bioactive substances and the non-polymeric carrier material. Such an interaction can adversely affect the physical and chemical characteristics of the composition resulting in undesired degradation of non-polymeric material and generation of impurities of the bioactive substance. The instability of the carrier material and the bioactive substance in the formulation will prevent the preparation of a suitable composition for storage with a reasonable shelf-life and for use of the formulation to form a consistent depot upon administration with desired release characteristics.
In addition, due to the hydrophobic nature of the non-polymeric carrier material, many bioactive agents, especially hydrophilic peptides and proteins with their charged and polar characteristics, may not be compatible with the non-polymeric carrier material, resulting in an unstable liquid formulation. Phase separation has been commonly observed when hydrophobic non-polymeric carrier materials are combined with an uncomplexed bioactive substance or its simple salt, such as acetate or hydrochloride salt. The phase separation during formulation, storage and in situ depot formation results in a non-homogeneous formulation or depot that leads to uncontrolled release characteristics. In addition, an initial burst release is the typical characteristic of this type of liquid formulations as evidenced in the prior art U.S. Pat. Nos. 5,747,058 and 5,968,542. The uncontrollable initial burst may not be desirable, especially for bioactive substances with a narrow therapeutic index.
Therefore, there is a need to develop a controlled release composition that will prevent or minimize undesirable interactions between the non-polymeric carrier materials and bioactive substances. There is also a need to develop a controlled release composition that can be formulated and stored as a single-phase homogeneous composition of non-polymeric carrier material and bioactive substance. There is a further need to develop such a single-phase homogeneous composition that will provide a depot with a low initial burst release.